This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The best understood Cullin-RING E3 ubiquitin ligase (CRL) is the SCF ubiquitin ligase, composed of Cul1, Skp1 and a member of the F-box family of proteins. Skp1 serves as an adaptor that simultaneously binds sequences near the N-terminus of Cul1 and the F-box motif of an F-box protein. In turn, F-box proteins contain additional protein interaction domains that recruit the substrate into a Cul1-Skp1-F-box protein complex, thereby facilitating ubiquitination of the target via the catalytic core assembled on the C-terminus of Cul1. In contrast, Cul3 employs BTB proteins as substrate specific adaptor. "BTB" is a protein interaction/dimerization domain that is structurally homologous to the cullin-binding region of Skp1, and that binds Cul3 via motifs analogous to those in the Skp1-Cul1 complex. Many BTB-domain proteins also contain additional protein interaction domains, some of which have been shown to recruit ubiquitination targets. Thus, BTB proteins are thought to merge the functional properties of Skp1or EloC and their F-box or SOCS-box partners into a single polypeptide chain, without an intervening F- or SOCS- box. The human genome encodes more than 150 proteins with recognizable BTB domains, often in combination with MATH, Kelch, or other interaction domains. BTB proteins containing MATH and Kelch domains have been linked to substrate targeting by Cul3, although it is unclear precisely how many BTB proteins engage Cul3 in vivo. Also, little is known about how MATH domains select targets for ubiquitination by CRLs. The MATH domain, present in numerous diverse proteins, is most frequently found linked to a C-terminal BTB domain. Indeed, the MATH-BTB module is the 10th most abundant of 2-domain combinations encoded by 131 genomes.